Activation of Invariant Natural Killer T Cells Redirects the Inflammatory Response in Neonatal Sepsis

Abstract

Sepsis is the third leading cause of death in the neonatal population, due to susceptibility to infection conferred by immaturity of both the innate and adaptive components of the immune system. Invariant natural killer T (iNKT) cells are specialized adaptive immune cells that possess important innate-like characteristics and have not yet been well-studied in septic neonates. We hypothesized that iNKT cells would play an important role in mediating the neonatal immune response to sepsis. To study this, we subjected 5- to 7-day-old neonatal C57BL/6 mice to sepsis by intraperitoneal (i.p.) cecal slurry (CS) injection. Thirty hours prior to or immediately following sepsis induction, pups received i.p. injection of the iNKT stimulator KRN7000 (KRN, 0.2 µg/g) or vehicle. Ten hours after CS injection, blood and tissues were collected for various analyses. Thirty-hour pretreatment with KRN resulted in better outcomes in inflammation, lung injury, and survival, while immediate treatment with KRN resulted in worse outcomes compared to vehicle treatment. We further analyzed the activation status of neonatal iNKT cells for 30 h after KRN administration, and showed a peak in frequency of CD69 expression on iNKT cells and serum IFN-γ levels at 5 and 10 h, respectively. We then used CD1d knockout neonatal mice to demonstrate that KRN acts through the major histocompatibility complex-like molecule CD1d to improve outcomes in neonatal sepsis. Finally, we identified that KRN pretreatment exerts its protective effect by increasing systemic levels of TGF-β1. These findings support the importance of iNKT cells for prophylactic immunomodulation in neonates susceptible to sepsis.

FAM134B-mediated endoplasmic reticulum autophagy protects against sepsis myocardial injury in mice

“…This is a limitation of our study and should be part of future research work. Sepsis is a systemic inflammatory response syndrome caused by infection [ 22 , 23 ]. The release of inflammatory cytokines plays a crucial role in the process of sepsis myocardial injury [ 24 ].…”

Recombinant human thrombomodulin attenuated sepsis severity in a non-surgical preterm mouse model

“…Effect of rhTM on the severity of sepsis. We randomly assigned mouse pups into four groups: non-septic control (vehicle [Veh]-pretreated normal saline IP administration, Veh-Veh) group, Veh-treated septic (Veh-CS) group, and rhTM pretreated septic (rhTM3-CS or rhTM10-CS) groups, based on the method used in a prior study 24 .…”

Protective Role of an Initial Low-Dose Septic Challenge against Lethal Sepsis in Neonatal Mice: A Pilot Study

“…From the perspective of direct activation of immune cells, Bolognese et al have reported a protective effect of activating Invariant Natural Killer T (iNKT) cells in neonatal sepsis. In their study, intraperitoneal injection of the iNKT stimulator KRN7000 30 h prior to sepsis induction resulted in better outcomes in inflammation, lung injury, and survival by increasing systemic levels of TGF-β1 [28]. All these studies have illustrated that preconditioning the immune response is effective in sepsis protection, even in neonatal mice.…”